Antimalarial drugs are frequently used to prevent malaria in pregnancy, when infection can threaten the health of mothers and their unborn babies. We propose to conduct a randomized controlled trial comparing two very different drug intervention strategies that have both been shown to prevent the sequelae of malaria in pregnancy: continuous weekly prophylaxis and intermittent preventive treatment (IPT). These strategies have never been assessed using the same drug in a direct comparative trial in the absence of significant drug resistance. We have a unique opportunity to compare these strategies in Malawi, where we recently discovered that twelve years after chloroquine was withdrawn due to high rates of resistance, chloroquine-susceptible parasites predominate and chloroquine is once again an effective agent to treat malaria. Chloroquine can be used during pregnancy as weekly prophylaxis or intermittent preventive therapy. In the proposed study, our aims are (1) to compare the efficacy of chloroquine as weekly prophylaxis vs. IPT in the prevention of pregnancy-associated malaria and its sequelae, (2) to compare the effect of these treatment strategies on antimalarial drug resistance and (3) to assess the impact of the origin and timing of malaria infections the sequelae of malaria in pregnancy. RELEVANCE: This study will provide important information for the future use of antimalarial medication and other interventions for the prevention of malaria in pregnancy. We will examine how and when to prevent pregnancy-associated malaria to protect mothers and their newborns and also avoid the spread of drug resistance.